The laboratory focuses on two immunology-related areas. The first concerns the properties and function of IA-2 and IA-2 which are major autoantigens in type 1 diabetes and transmembrane proteins of dense core secretory vesicles. These proteins are present in most of the neuroendocrine cells in the body. Knockout and knock down technology has shown that these proteins affect the secretion of hormones (e.g., insulin) and neurotransmitters. Current studies are concerned with the effect of IA-2 and IA-2beta on the secretion of these hormones and neurotransmitters and how they affect a variety of physiologic processes. In addition, the role of micro RNA's in the expression of the genes encoding these proteins is being examined. The second area concerns polyreactive antibodies. Polyreactive antibodies are a major component of the natural antibody repertoire and bind to a variety of structurally unrelated molecules. These antibodies are thought to provide a first line of defense against bacterial infections and play a major role in the clearance of apoptotic cells. What trigger the secretion of these antibodies has remained an enigma. Using a surrogate assay for measuring polyreactive antibodies in mice, we found that about 50% of serum IgM is polyreactive and simulation of certain toll-like receptors results in a substantial increase in the secretion of polyreactive antibodies. Infection with a virus or tissue damage induced by a toxin similarly leads to an increase in polyreactive antibodies. Other factors involved in the secretion of polyreactive antibodies are now under study.